Process for the production of new efficacious p-amino-benzene-sulphamide derivativessuitable for injection purposes



Patented Jan. 4, 1944 PROGES S. FOR.,THE PRODUCTION..OF NEW 'EEFICACIQUS p AMINO eBENZENE SULPI-I- AMIDE DERIVATIVES SUITABLE FOR IN- JEGTION' PURPOSES @znan Fiild (Bud e yr veste n the .AliemP-mperty Custodian No'Drawing. Application February 5, 1938, Serial '--No.'-188,9'58. In Hungary February13, 1937 7 7- Claims.

Chemical compounds of the amino benzenesulphamide typeareextensively used in therapy, particularly for diseases due to streptococcic infection. However, p-amino-benzene-sulphamide is only to avery slight extent. soluble in water and it is therefore unsuitable" for-preparing solutionsof the necessary concentration." Neither are the salts formed by the said compounds with acids,- suitable for preparing solutions intended possess astrong acid property.

formaldehyde sulphoxylate.

for injection, because their aqueous solutions e- C ugo 0 8 Of p y at p mol of amino-benzene-sulphamide. Such a reac- According to my-presentinvention itis possible tion mixture has an alkaline reaction, owingv to to obtainp-amino -benzene sulphamide yderivathe hydrolysisof the excess of sulphoxylate. In tives readily soluble in water and suitable for inthis case the heating of the reaction mixture (50 jection purposes, if p-amino-benzene-sulphagrams of ----p-amino-benzene-sulphon-amide, '75 mide,, or,su ch,,derivatives of the same as result grams of "formaldehyde sodium sulphoxylate, from substitutions effected in the nucleus or in free from'water of crystallisation, and100 ccm. the nitrogen atoms are subjected to the action of of water) should be continued in a water bath of '70 to 90 C. for about hours.

It has been found to be particularly advanta- 20 formed during this process is likewise most easily geous to perform the reaction of the formaldesoluble in water, but when acidified with mineral hyde sulphoxylate in the presence of about 1 mol acids no free acid will precipitate. The isolation of alkali metal hydroxyde, in which case prodof the product from this reaction mixture is ucts, extremely soluble in water, are formed, preferably effected by pouring it into a quantity which can be easily isolated from the reaction of absolute alcohol amounting to between 6 and mixture by addition of mineral acid, whereupon 10 times the quantity of the reaction mixture, an acid difficulty soluble in water will separate whereupon the product precipitates in the form If this acid is filtered off, washed with water and of a gummy mass. then neutralized by means of alkali metal hystand for a while, the liquid is decanted, fresh droxides, as for instance, by sodium hydroxide, absolute alcohol is poured to the gummy residue, an aqueous solution of the product results in whereupon the latter becomes converted into a which product practically two atoms of sulphur white powdery mass. correspond to two atoms of nitrogen, i. e., in very easily soluble in water is obtained; the W ic product 1 H101 f amino-benzene-sulchemical analysis shows the presence of about 3 phamide is connected with 1 mol of formaldehyde 3 atoms of sulphur for each two atoms of nitrogen, sulphoxylate. Thus for instance 50 grams of i. e., in this product 2 groups of sulphoxylate are p-amino-benzene-sulphamide are dissolved in a joined to 1 mol of amino-benzene-sulphamide. mixture of 70 ccm. of water and of 20 to com. The product contains varying amounts of water O a 47 D 061113 y Volume um hydroxide soluof crystallisation. About 3 mols of water of crystion by heating in a water-bath, and after 0001- tallisation were found. I ing a solution of 50 to 100 grams of formalde- The presence of the sulphoxylate groups can hyde sodium-sulphoxylate in 100 to 200 ccm. of easily be shown by titration by means of indigo water is added. This mixture is heated at a temcarmine. perature of to 80 C. for one hour, then the 45 The chemical compounds solution is cooled and to the filtered solution groups of'sulphoxylate will offer in its aqueous hydrochloric acid is added until a filtered test solutions much greater a resistance to the effects portion will not produce any further precipitate of air than the derivatives containing only one on the addition of hydrochloric acid. The presu phoxylate group. The reaction of the solucipitate is collected on a suction funnel, prefer- 50 tions to litmus is alkaline, but to phenol phthaably excluded from air, and washed with water. ei p t y neutral thus remainin Within The wet acid when neutralised with a solution a reaction range very suitable for solutions i of sodium hydroxide, gives a solution of the tended for injection purpose. sodium salt which is easily soluble in water. It The products of the proces are employed for is, however, also possible to dry the acid in vacuo over phosphoruspentoxide-and to effect theformation of the salt in an alcoholic medium.

If no sodium hydroxide is employed during the action of the sulphoxylate, only a very slow reaction will t'ake-plaoebetween the sulphoxylate and the amino-benzene-sulphamides (amino-benzene sulphamide, "benzylamino -benzene sulphamide, amino-benzene-disulphamide, etc). In this case it will be preferable to employ the sulphoxylate in The product After allowing the mixture to After drying, a substance containing two pharmaceutical purposes.

What I claim is:

1. Para -(N sodium methylene sulphinate) amino benzene-sulphonamide.

2. The process of producing new compounds which comprises reacting sulphanilamide with sodium-forma1dehyde-sulphoxy1atein equimolecul'ar proportions and in an aqueous medium to produce the N-methylene sulphinate of sulphanilamide, the reaction being efiected in an alkaline solution.

3. The process of producing new compounds which comprises reacting sulphanilamide with sodium-formaldehyde-sulphoxylate in equimolecular proportions and in an aqueous medium in the presence of a mol of alkali-metal hydroxide to produce the N-methylene sulphinate of sulphanilamide. e

4. A method of producing new compounds from sulphanilamide and an alkali metal-formaldehyde-sulphoxylate comprising heating an equimolecular mixture of sulphanilamide and alkali metal-formaldehyde-sulphoxylate in an aqueous medium in the presence of an alkali-metal hydroxide for a period of time sumcient to effect a combining reaction between the sulphanilamide and the alkali metal-formaldehyde-sulphoxylate, cooling the reaction mixture, filtering, adding a mineral acid to the filtrate to form a precipitate, and separating the precipitate formed.

5. A method of producing new compounds from sulphanilamide and an alkali metal-formaldehyde-sulphoxylate comprising heating an equimolecular mixture of sulphanilamide and alkali metal-formaldehyde-sulphcxyiate in an aqueous medium in the presence of an alkali-metal hydroxide for a period of time sumcient to efiect a combining reaction between the sulphanilamide and the alkali metal-formaldehyde-sulphoxylate, cooling the reaction mixture, filtering, adding a mineral acid to the filtrate to form a precipitate, separating the precipitate formed, and dissolving the precipitate in an alkali-metal hydroxide solution.

6. A method of producing new compounds from sulphanilamide and an alkali metal-formalde hyde-sulphoxylate comprising heating an equimolecular mixture of sulphanilamide and alkali metal-formaldehyde-sulphoxylate in an aqueous medium in the presence of an alkali-metal hydroxide for a period of time suflicient to effect a combining reaction between the sulphanilamide and the alkali metal-formaldehyde-sulphoxylate, cooling the reaction mixture, adding a hydrochloric acid solution thereto to form a precipitate of the acid component of the compound produced by the reaction, and separating the precipitate.

'7. A method of producing new compounds from sulphanilamide and an alkali metal-formaldehyde-sulphoxylate comprising heating an equimolecular mixture of sulphanilamide and alkali metal-formaldehyde-sulphoxylate in an aqueous medium in the presence of an alkali-metal hydroxide for a period of time suificient to efiect a combining reaction between the sulphanilamide and the alkali metal-formaldehyde-sulphoxy1ate, cooling the reaction mixture, adding a hydrochloric acid solution thereto to form a precipitate of the acid component of the compound produced by the reaction, separating the precipitate, and dissolving the precipitate in an alkali-metal hydroxide solution to form an alkali-metal salt of the acid form of said compound.

ZOLTAN Form. 

